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[Cancer Research 63, 3805-3811, July 1, 2003]
© 2003 American Association for Cancer Research

Tumor Biology

Intravascular Metastatic Cancer Cell Homotypic Aggregation at the Sites of Primary Attachment to the Endothelium1

Vladislav V. Glinsky2, Gennadi V. Glinsky, Olga V. Glinskii, Virginia H. Huxley, James R. Turk, Valeri V. Mossine, Susan L. Deutscher, Kenneth J. Pienta and Thomas P. Quinn

Departments of Biochemistry [V. V. G., V. V. M., S. L. D., T. P. Q.], Physiology [O. V. G., V. H. H.], and Veterinary Biomedical Sciences [J. R. T., V. H. H.], University of Missouri, Columbia, Missouri 65211; Harry S. Truman Memorial Veterans Hospital [V. V. G., O. V. G., S. L. D.], Columbia, Missouri 65201; Sidney Kimmel Cancer Center and Metastat, Inc. [G. V. G.], San Diego, California 92121; and Departments of Internal Medicine and Urology [K. J. P.], University of Michigan, Ann Arbor, Michigan 48109

The two major theories of cancer metastasis, the seed and soil hypothesis and the mechanical trapping theory, view tumor cell adhesion to blood vessel endothelia and cancer cell aggregation as corresponding key components of the metastatic process. Here, we demonstrate in vitro, ex vivo, and in vivo that metastatic breast and prostate carcinoma cells form multicellular homotypic aggregates at the sites of their primary attachment to the endothelium. Our results suggest that metastatic cell heterotypic adhesion to the microvascular endothelium and homotypic aggregation represent two coordinated subsequent steps of the metastatic cascade mediated largely by similar molecular mechanisms, specifically by interactions of tumor-associated Thomsen-Friedenreich glycoantigen with the ß-galactoside-binding protein, galectin-3. In addition to inhibiting neoplastic cell adhesion to the endothelium and homotypic aggregation, disrupting this line of intercellular communication using synthetic Thomsen-Friedenreich antigen masking and Thomsen-Friedenreich antigen mimicking compounds greatly affects cancer cell clonogenic survival and growth as well. Thus, ß-galactoside-mediated intravascular heterotypic and homotypic tumor cell adhesive interactions at the sites of a primary attachment to the microvascular endothelium could play an important role during early stages of hematogenous cancer metastasis.




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